Reversible manipulation of apoptosis sensitivity in cultured hepatocytes by matrix-mediated manipulation of signaling activities

Methods in Molecular Biology
Patricio GodoyJan G Hengstler

Abstract

Hepatocytes in culture are a valuable tool to investigate mechanisms involved in the response of the liver to cytokines. However, it is well established that hepatocytes cultured as monolayers on dried stiff collagen dedifferentiate, loosing specialized liver functions. In contrast, softer matrix systems like gelled collagen help to preserve these structural and functional features. We show that the de-differentiation process induced in conventional dry collagen is a reversible consequence of a specific signaling network constellation triggered by the extracellular matrix that results in apoptosis resistance. A dried stiff collagen activates Akt and ERK1/2 pathways that results in apoptosis resistance. In contrast to stiff collagen, a soft collagen gel does not activate these pathways keeping the hepatocytes in a state where they remain sensitive to TGF-beta-induced apoptosis. Finally, we show that matrix-induced apoptosis resistance is reversible by re-plating cells from dried stiff to soft gel collagen. Practical consequences of these observations are that differentiated functions of hepatocytes, such as metabolism, endocytosis, and apoptosis, should be studied in hepatocyte sandwiches. On the other hand, proliferation and re...Continue Reading

Citations

Dec 2, 2015·Archives of Toxicology·Klaus Golka
Nov 4, 2015·Archives of Toxicology·H M Bolt, R Marchan
Aug 19, 2016·Molecular Biology of the Cell·Sujith V W WeerasingheM Bishr Omary
Aug 16, 2012·Archives of Toxicology·P GodoyH M Bolt
Nov 6, 2014·Archives of Toxicology·Ahmed Ghallab, H M Bolt
Jun 12, 2012·Archives of Toxicology·R Marchan, H M Bolt
Jun 19, 2012·Archives of Toxicology·P Godoy, H M Bolt
Oct 31, 2014·Archives of Toxicology·J G HengstlerH M Bolt
Mar 15, 2012·Archives of Toxicology·R MarchanH M Bolt
Nov 17, 2014·Archives of Toxicology·Marianna GrinbergJan G Hengstler
Dec 5, 2018·Archives of Toxicology·Marianna GrinbergJan G Hengstler

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis